Professional Documents
Culture Documents
Guia SUPAC
Guia SUPAC
CMC 9
Revision 1
Guidance for Industry
SUPAC-IR/MR: Immediate Release and
Modified Release Solid Oral Dosage Forms
(Internet) http://www.fda.gov/cder/guidance/index.htm
CMC 9
Revision 1
TABLE OF CONTENTS
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
IV. GRANULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
V. DRYING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
VIII. COATING/PRINTING/DRILLING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
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GUIDANCE FOR INDUSTRY 1
I. INTRODUCTION
The document should be used in conjunction with the SUPAC-IR and SUPAC-MR guidance
documents in determining what documentation should be submitted to FDA regarding equipment
changes made in accordance with the recommendations in these guidance documents. The
SUPAC guidance documents define (1) levels of change; (2) recommended chemistry,
manufacturing, and controls tests for each level of change; (3) in vitro dissolution tests and/or in
vivo bioequivalence tests for each level of change; and (4) documentation that should support the
change for new drug applications (NDAs) and abbreviated new drug applications (ANDAs).
This document is only an aid and, in some cases, specific equipment may not be listed. It does,
however, include a representative list of equipment commonly used in the industry. The guidance
does not address equipment that has been modified by a pharmaceutical manufacturer to fit its
specific needs. If questions arise in using this guidance document please contact the appropriate
1
This guidance has been prepared under the auspices of the Chemistry, Manufacturing, and Controls
Coordinating Committee in the Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs
(ORA) at the Food and Drug Administration with the assistance of the International Society of Pharmaceutical
Engineering (ISPE). This guidance represents the Agency's current thinking on equipment changes under SUPAC-IR
and SUPAC-MR. It does not create or confer any rights for or on any person and does not operate to bind the FDA or
the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute,
regulations or both.
reviewing office at CDER.
Although this guidance does not discuss validation, any equipment changes should be validated in
accordance with current good manufacturing practices (cGMPs) and the resulting data will be
subject to examination by field investigators during routine GMP inspections. The information is
presented in broad categories of unit operation (blending and mixing, drying, particle size
reduction/separation, granulation, unit dosage, coating and printing, soft gelatin capsule
encapsulation). Definitions and classification are provided. For each operation, a table is
presented that categorizes equipment by class (operating principle) and subclass (design
characteristic). Examples are given within the subclasses.
Equipment within the same class and subclass would be considered to have the same design and
operating principle under SUPAC-IR and SUPAC-MR. Therefore, for example, a change from
one type of diffusion mixer (e.g, V-blender from manufacturer A) to another diffusion mixer (e.g.,
V-blender from manufacturer B) generally would not represent a change in operating principle
and would, therefore, be considered to be the same under either SUPAC-IR or SUPAC-MR.
A change from equipment in one class to equipment in a different class would usually be
considered a change in design and operating principle. For example, a change from a V-blender
to a ribbon blender demonstrates a change in the operating principle from diffusion blending to
convection blending and would be considered to be different under either SUPAC-IR or SUPAC-
MR.
Applicants should carefully consider and evaluate on a case-by-case basis changes in equipment
that are in the same class, but different subclass. In many situations, this type of change in
equipment would be considered similar. For example, within the Blending and Mixing section,
under the Diffusion Mixers Class, a change from a V-blender (sub-class) to a Bin tumbler (sub-
class) represents a change within a class and between sub-classes. Provided the manufacturing
process with the new equipment is validated, this change would likely not need a pre-approval
supplement. The applicant should have available at the time of the change the scientific data and
rationale used to make this determination. This information is subject to FDA review at its
discretion. It is up to the applicant to determine the filing requirement.
This guidance will be updated as needed to reflect the introduction and discontinuation of specific
types of manufacturing equipment. Manufacturers of equipment are encouraged to help keep the
document current by communicating changes to the Agency and by making suggestions regarding
what equipment should be considered to be within the same class or subclass. The submitted
information will be reviewed by FDA and incorporated in an updated guidance document as
appropriate.
2
A. Definitions
1. Unit Operations
2. Operating Principles
b. Impact Milling
3
Particles are reduced in size by high-speed mechanical impact or
impact with other particles; also known as milling, pulverizing, or
comminuting.
c. Cutting
d. Compression Milling
e. Screening
f. Tumble Milling
g. Separating
Particles are segregated based upon particle size alone and without
any significant particle size reduction. This process commonly is
referred to as screening or bolting.
B. Equipment Classifications
Fluid energy mill subclasses have no moving parts and primarily are
distinguished from one another by the configuration and/or shape of their
chambers, nozzles, and classifiers.
C Tangential Jet
C Loop/Oval
C Opposed Jet
C Opposed Jet with Dynamic Classifier
C Fluidized Bed
C Fixed Target
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C Moving Target
2. Impact Mills
Impact mill subclasses primarily are distinguished from one another by the
configuration of the grinding heads, chamber grinding liners (if any), and
classifiers.
3. Cutting Mills
Although cutting mills may differ from one another in whether the knives
are movable or fixed and in the classifier configuration, no cutting mill
subclasses have been identified.
4. Compression Mills
Although compression mills may differ from one another in whether one or
both surfaces are moving, no compression mill subclasses have been
identified.
5. Screening Mills
C Rotating Impeller
C Rotating Screen
C Oscillating Bar
6. Tumbling Mills
C Ball Media
C Rod Media
C Vibrating
5
7. Separators
C Vibratory/Shaker
C Centrifugal
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Table 1 Unit Operation - Particle Size Reduction
Cage Stedman
7
Table 1 Unit Operation - Particle Size Reduction (cont.)
Vibrating Sweco
Centrifugal AZO
Kason
Kemutec
Sweco
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III. BLENDING AND MIXING
A. Definitions
1. Unit Operations
2. Operating Principles
b. Convection Mixing
c. Pneumatic Mixing
B. Equipment Classifications
C V-blenders
C Double Cone Blenders
C Slant Cone Blenders
C Cube Blenders
C Bin Blenders
C Horizontal/Vertical/Drum Blenders
C Static Continuous Blenders
C Dynamic Continuous Blenders
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2. Convection Mixers
C Ribbon Blenders
C Orbiting Screw Blenders
C Planetary Blenders
C Forberg Blenders
C Horizontal Double Arm Blenders
C Horizontal High Intensity Mixers
C Vertical High Intensity Mixers
C Diffusion Mixers (Tumble) with Intensifier/Agitator
3. Pneumatic Mixers
10
Table 1 Unit Operation - Blending and Mixing
11
Table 1 Unit Operation - Blending & Mixing (cont.)
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Table 1 Unit Operation - Blending & Mixing (cont.)
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IV. GRANULATION
A. Definitions
1. Unit Operations
2. Operating Principles
a. Dry Granulation
e. Extrusion Granulation
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gradient.
f. Rotary Granulation
B. Equipment Classification
1. Dry Granulator
C Slugging
C Roller Compaction
15
Wet low-shear granulator subclasses primarily are distinguished by the
geometry and design of the shear inducing components; shear can be
induced by rotating impeller, reciprocal kneading action, or convection
screw action.
C Planetary
C Kneading
C Screw
5. Extrusion Granulator
C Radial or Basket
C Axial
C Ram
C Roller, Gear, or Pelletizer
6. Rotary Granulator
C Open
C Closed
Although fluid bed granulators may differ from one another in geometry,
operating pressures, and other conditions, no fluid bed granulator
subclasses have been identified.
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Although spray dry granulators may differ from one another in geometry,
operating pressures, and other conditions, no spray dry granulator
subclasses have been identified.
Note:
If a single piece of equipment is capable of performing multiple discrete unit operations (mixing,
granulating, drying), the unit was evaluated solely for its ability to granulate. If multifunctional
units were incapable of discrete steps (fluid bed granulator/drier), the unit was evaluated as an
integrated unit.
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Table 1 Unit Operation - Granulation
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Table 1 Unit Operation - Granulation (cont.)
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V. DRYING
A. Definitions
1. Unit Operation
2. Operating Principles
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carried away by the drying gases. The solids are fully expanded and
so widely separated that they exert essentially no influence on one
another.
Drying in which the water vapor sublimes from the product after
freezing.
i. Gas Stripping
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slightly expands the bed enough to flow one particle over one
another. This process commonly is referred to as microwave
drying.
B. Equipment Classifications
C Rotating Tray
C Horizontal Vibrating Conveyor
Although fluid bed dryers may differ from one another in geometry,
operating pressures, and other conditions, no fluidized solids bed dryer
subclasses have been identified.
Although spray dryers may differ from one another in geometry, operating
pressures, and other conditions, no spray dryer subclasses have been
identified.
Although flash dryers may differ from one another in geometry, operating
pressures, and other conditions, no flash dryer subclasses have been
identified.
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technology for moving the solids bed.
C Paddle
C Rotary (Tumble)
C Agitation
No indirect heating, static solids bed shelf dryer subclasses have been
identified.
9. Gas Stripping
Although gas stripping dryers may differ from one another in geometry,
shape of agitator, and how fluidizing gas is moved through the bed, no gas
stripping dryer subclasses have been identified.
Note:
If a single piece of equipment is capable of performing multiple discrete unit operations (mixing,
granulating, drying), the unit was evaluated solely for its ability to dry. The drying equipment was
sorted into similar classes of equipment, based upon the method of heat transfer and the dynamics
of the solids bed.
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Table 1 Unit Operation - Drying
Belt Despatch
Proctor & Schwartz
24
Table 1 Unit Operation - Drying (cont.)
Agitation L. B. Bohle
Diosna
GEI-Collette (GEI International)
Krauss-Maffei
Processall
Vrieco-Nauta (Hosokawa)
Zanchetta (Romaco)
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VI. UNIT DOSING
A. Definitions
1. Unit Operation
Unit Dosing: The division of a powder blend into uniform single portions
for delivery to patients.
2. Operating Principles
a. Tabletting
b. Encapsulating
c. Powder Filling
B. Equipment Classifications
1. Tablet Press
Tablet press subclasses primarily are distinguished from one another by the
method that the powder blend is delivered to the die cavity. Tablet presses
can deliver powders without mechanical assistance (gravity), with
mechanical assistance (power assisted), by rotational forces (centrifugal),
and in two different locations where a tablet core is formed and
subsequently an outer layer of coating material is applied (compression
coating).
C Gravity
C Power Assisted
C Centrifugal
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C Compression Coating
2. Encapsulator
C Auger
C Vacuum
C Vibratory
C Dosing Disk
C Dosator
3. Powder Filler
C Vacuum
C Auger
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Table 1 Unit Dosing
Vacuum Perry
Auger All-Fill
Calumatic
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VII. SOFT GELATIN CAPSULES
A. Definitions
1. Unit Operations
b. Fill Mixing: The mixing of either liquids or solids with other liquids
to form a solution; blending of limited solubility solid(s) with a
liquid carrier and suspending agents used to stabilize the blend to
form a suspension; or the uniform combination of dry inert and
drug active substances to form a dry powder fill suitable for
encapsulation. The reader should refer to the other sections of this
document for dry fill manufacture.
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equipment. This equipment will not be discussed in this guidance
document.
2. Operating Principles
a. Mixing
b. Deaggregation
c. Deaeration
The removal of entrapped air from either the gel mass or fill
material, solution or suspension. This process can take place in
either the mixing vessel, through the application of vacuum, or a
separate off-line step.
d. Holding
2
Carstensen, J. T., “Theory of Pharmaceutical Systems, Volume 11 Heterogeneous Systems," Academic Press,
New York, NY, 1973, p 51.
30
e. Encapsulation
f. Inspection/Sorting
g. Printing
B. Equipment Classifications
2. Deaggregators
C Rotor/Stator
3
Lachman, L., H. A. Lieberman, and J. L. Kanig (Eds.), The Theory and Practice of Industrial Pharmacy,
Chapter 3, p. 359 (Stanley, J. P.), Philadelphia: Lea & Febiger, 1971.
Tyle, P. (Ed.), Specialized Drug Delivery Systems, Manufacturing and Production Technology, Chapter 10, p. 409
(Wilkinson, P.K.and F.S. Hom), New York: M. Dekker, 1990.
Porter, S., Remington’s Pharmaceutical Sciences, Edition 18, Chapter 89, pp. 1662 - 1665, Easton, Penn.: Mack
Publishing Co.
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C Roller
C Cutting Mills
C Stone Mills
C Tumbling Mills
3. Deaerators
C Vacuum Vessel
C Off Line/In Line
4. Holding Vessels
Although holding vessels may differ from one another, based upon whether
they are jacketed, with and without integrated mixing capabilities, no
holding vessel subclasses have beeen identified.
5. Encapsulators
6. Inspection/Sorting
C Belt
C Vibratory
C Roller
C Rotary Table
C Electromechanical
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Table 1 Unit Operation - Soft Gelatin Capsules
Planetary Aaron
Aeschbach
AMF
GEI-Collette (GEI International)
Hobart
Jaygo
Littleford Day
Ross
Vrieco
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Table 1 Unit Operation - Soft Gelatin Capsules (cont.)
Roller Stokes-Merrill
Holding Vessels Jacketed Vessel with and without GEI-Kreiger (GEI International)
Mixing System Koruma (Romaco)
Lee Industries
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Table 1 Unit Operation - Soft Gelatin Capsules (cont.)
Vibratory Stokes
Roller Maschimpex
ElectroMechanical Mocon
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VIII. COATING/PRINTING/DRILLING
A. Definitions
1. Unit Operation
36
the application of a contrasting colored polymer (ink) onto the
surface of a capsule or tablet, or by the use of laser etching.
2. Operating Principles
a. Pan Coating
b. Gas Suspension
d. Dip Coating
e. Electrostatic Coating
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substrate. The coating material containing oppositely charged ionic
species is sprayed onto the substrate.
f. Compression Coating
g. Ink-Based Printing
h. Laser Etching
i. Drilling
B. Equipment Classification
1. Pan Coating
2. Gas Suspension
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by which the coating is applied to the substrate.
C Fluidized Bed
C Spray Congealing/Drying
4. Dip Coating
Because of the custom design associated with this class of coating, no dip
coating subclasses or examples have been identified.
5. Electrostatic Coating
6. Compression Coating
7. Ink-Based Printing
C Offset
C Ink Jet
Although laser etching systems may differ from one another, no laser
etching subclasses have been identified.
9. Drilling
The method of producing the laser pulse that ablates the hole(s) is of no
consequence to the physical-chemical properties of the product. Therefore,
no dosage form drilling equipment subclasses have been identified.
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Table 1 Unit Operation - Coating Equipment
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Table 2 Unit Operation - Printing Equipment
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